JPS6157828B2 - - Google Patents
Info
- Publication number
- JPS6157828B2 JPS6157828B2 JP952279A JP952279A JPS6157828B2 JP S6157828 B2 JPS6157828 B2 JP S6157828B2 JP 952279 A JP952279 A JP 952279A JP 952279 A JP952279 A JP 952279A JP S6157828 B2 JPS6157828 B2 JP S6157828B2
- Authority
- JP
- Japan
- Prior art keywords
- present
- formula
- compound
- administered
- represented
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims description 15
- -1 nicotinoyl group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 208000017170 Lipid metabolism disease Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DJWYOLJPSHDSAL-UHFFFAOYSA-N Pantethine Natural products OCC(C)(C)C(O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)C(O)C(C)(C)CO DJWYOLJPSHDSAL-UHFFFAOYSA-N 0.000 description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- DJWYOLJPSHDSAL-ROUUACIJSA-N pantethine Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO DJWYOLJPSHDSAL-ROUUACIJSA-N 0.000 description 3
- 229960000903 pantethine Drugs 0.000 description 3
- 235000008975 pantethine Nutrition 0.000 description 3
- 239000011581 pantethine Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000003307 slaughter Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 208000007082 Alcoholic Fatty Liver Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010016262 Fatty liver alcoholic Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000026594 alcoholic fatty liver disease Diseases 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 208000010706 fatty liver disease Diseases 0.000 description 2
- 238000000434 field desorption mass spectrometry Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000021588 free fatty acids Nutrition 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 239000004129 EU approved improving agent Substances 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は一般式（Ｉ）
（式中、R1，R2，R′1およびR′2は水素原子又はニ
コチノイル基を意味する。但し、R1，R2，R′1お
よびR′2が同時に水素原子であることはない。）で
示されるニコチノイルパンテチン誘導体に関す
る。
本発明化合物は優れた脂質代謝障害改善作用を
呈し、高脂血症、動脈硬化症、糖尿病、アルコー
ル性脂肪肝等の脂質代謝障害に基因する諸症状の
改善剤として有用である。
本発明の式（Ｉ）で示される目的化合物は、例
えばパンテチンとニコチン酸クロライドを脱酸剤
の存在下、適度に加温して反応させることにより
製することが出来る。脱酸剤としては、例えばピ
リジン等の有機第三級アミンが繁用される。好ま
しい反応温度としては40〜50℃を挙げうる。又、
所望により反応溶媒を使用することが可能であ
り、その場合、反応に関与しない有機溶媒、例え
ばベンゼン類、ハロゲン化炭化水素類、エーテル
類などが繁用される。このようにして製した式
（Ｉ）で示される目的化合物は、通常の単離精製
操作、例えばクロマトグラフイーなどによる単離
精製を実施することが出来る。
式（Ｉ）で示される本発明化合物は塩基性の基
を有し、場合により通常許容される酸付加塩とし
て取得することが可能である。なお、本発明化合
物はいずれも不斉炭素原子が存在するので、光学
活性体として製することも可能である。
本発明化合物の優れた脂質代謝障害改善作用
は、イー・エー・ホーザイン、ビー・ベクストン
の方法（バイオケミカル・フアーマコロジイー、
24巻、1859頁、1975年）に準じて作製した実験的
アルコール性脂肪肝ラツトによる血清脂質低下作
用試験等により確認された。即ち、実験動物とし
て一群６匹の６週令、雄性スプラーグ・ダウレイ
系ラツトを用い、アルコールの40%(V/V)水溶液
を10ml/Kg（略、アルコール３g/Kgに相当）ず
つ、屠殺当日を含めてその２日前から３日間連続
（最終日は午前10時に、その他の日は午後４時に
投与）、胃ゾンデにて経口投与し、本発明化合物
は0.5%(V/V)ツイーン80水溶液に充分均一に懸濁
後、屠殺当日を含めてその４日間から５日間連続
（毎日午前９時に投与）、胃ゾンデにて経口投与し
た。ラツトを屠殺（最終日の午後１時）後、総コ
レステロールをビー・ザツクの方法（アメリカ
ン・ジヤーナル・オブ・クリニカル・パソロジ
ー、27巻、583頁、1957年）、遊離脂肪酸をケー・
イタヤ、エム・ウイの方法（ジヤーナル・オブ・
リピド・リサーチ、６巻、16頁、1965年）でそれ
ぞれ測定した。表１に本発明化合物の中の代表化
合物として、
式
で表わされるＮ，N′−〔ジチオビス（エチレンイ
ミノカルボニルエチレン）〕ビス〔２，４−ジヒ
ドロキシ−３，３−ジメチルブチルアミド〕２，
2′，４，4′−テトラニコチネートについて試験し
た結果を正常ラツトの値を対照に例示する。
表１より、本発明化合物が優れた血清コレステ
ロールおよび遊離脂肪酸低下作用を呈することが
認められ、脂質代謝障害改善剤として非常に有用
であることが明白である。
The present invention relates to general formula (I) (In the formula, R 1 , R 2 , R′ 1 and R′ 2 mean a hydrogen atom or a nicotinoyl group. However, if R 1 , R 2 , R′ 1 and R′ 2 are hydrogen atoms at the same time, ). The compound of the present invention exhibits an excellent action to improve lipid metabolism disorders and is useful as an ameliorating agent for various symptoms caused by lipid metabolism disorders such as hyperlipidemia, arteriosclerosis, diabetes, and alcoholic fatty liver. The target compound represented by the formula (I) of the present invention can be produced, for example, by reacting pantethine and nicotinic acid chloride in the presence of a deoxidizing agent with appropriate heating. As the deoxidizer, organic tertiary amines such as pyridine are often used. A preferable reaction temperature is 40 to 50°C. or,
A reaction solvent can be used if desired, and in that case, organic solvents that do not participate in the reaction, such as benzenes, halogenated hydrocarbons, ethers, etc., are often used. The target compound represented by formula (I) thus produced can be isolated and purified by conventional isolation and purification operations, such as chromatography. The compound of the present invention represented by formula (I) has a basic group, and can be obtained as a generally acceptable acid addition salt in some cases. Note that since all of the compounds of the present invention have an asymmetric carbon atom, they can also be produced as optically active compounds. The excellent lipid metabolism disorder improving effect of the compound of the present invention was demonstrated by the method of E.A. Hozain and B. Bexton (Biochemical Pharmacology,
This was confirmed by a serum lipid-lowering effect test using experimental alcoholic fatty liver rats prepared in accordance with Vol. 24, p. 1859, 1975). That is, a group of 6 6-week-old male Sprague-Dowley rats were used as experimental animals, and 10 ml/Kg of a 40% (V/V) alcohol solution (equivalent to 3 g/Kg of alcohol) was administered on the day of slaughter. The compound of the present invention was administered orally through a gastric probe for 3 consecutive days starting 2 days before (administered at 10 a.m. on the last day and at 4 p.m. on other days), and the compound of the present invention was administered in a 0.5% (V/V) Tween 80 aqueous solution. After thoroughly and uniformly suspending the drug, it was orally administered using a gastric tube for 4 to 5 consecutive days (administered at 9:00 a.m. every day) including the day of slaughter. After slaughtering the rats (1 p.m. on the last day), total cholesterol was determined by the method of B. Zatsk (American Journal of Clinical Pathology, vol. 27, p. 583, 1957), and free fatty acids were determined by K.
Itaya, M Ui's Method (Journal of
Lipid Research, Vol. 6, p. 16, 1965). Table 1 shows the formula as a representative compound among the compounds of the present invention. N,N′-[dithiobis(ethyleneiminocarbonylethylene)]bis[2,4-dihydroxy-3,3-dimethylbutyramide]2,
The results of tests on 2',4,4'-tetranicotinate are illustrated with reference to normal rat values. From Table 1, it is clear that the compounds of the present invention exhibit excellent serum cholesterol and free fatty acid lowering effects, and are very useful as lipid metabolic disorder improving agents.
【表】
本剤の投与に際しては、種々の剤型、例えばカ
プセル、錠剤、散剤、注射剤等の任意の型に公知
の製剤技術により加工して使用することが可能で
ある。
本剤の投与量は投与方法によつても異なるが、
200〜2000mg／日／人の投与量で十分有効であ
る。
以下、実施例を挙げて本発明を説明する。
実施例 １
パンテチン6.50gをピリジン65mlに溶かし、こ
れにニコチン酸クロライド塩酸塩10.0gを加え、
40〜45℃に２時間加熱撹拌する。冷後、析出する
結晶を濾去し、次いで濾液を５％重曹水300mlに
注加後、酢酸エチルで抽出する。抽出液を水洗
し、乾燥して溶媒を留去する。残渣をシリカゲル
450gのカラムクロマトで処理し、展開後、クロ
ロホルム：メタノール（12：１）混合液で流出し
た部分よりＮ，N′−〔ジチオビス（エチレンイミ
ノカルボニルエチレン）〕ビス〔２，４−ジヒド
ロキシ−３，３−ジメチルブチルアミド〕２，
2′，４，4′−テトラニコチネートの無色粉末
7.10gを得る。
元素分析 C46H54N8O12S12
計算値 C56.65，H5.58，N11.49，S6.58
実験値 C56.26，H5.68，N10.98，S6.58
IRスペクトル（KBr法）
第１図参照
NMRスペクトル
δＣＤＣｌ３ ＴＭＳ；
1.30（12H，ｓ）
2.45（4H，ｍ）
2.70（4H，ｍ）
3.50（8H，ｍ）
4.38（4H，ｓ）
5.32（2H，ｓ）
7.50（8H，ｍ）
8.35（4H，ｍ）
8.84（4H，ｍ）
9.30（4H，ｍ）
フイールド・デソープシヨン・マススペクトル
（以下、FD―MSと略す。）
ｍ／ｅ＝975（Ｍ＋１）＋
実施例 ２
パンテチン5.54gをピリジン50mlに溶かし、こ
れにニコチン酸クロライド塩酸塩1.78gを加え、
40℃に１時間加熱撹拌する。次いで反応液にニコ
チン酸クロライド塩酸塩2.49gを追加し、更に２
時間40℃に加熱撹拌する。冷後、析出する結晶を
濾去し、次いで濾液を５％重曹水250mlに注加
後、酢酸エチルで抽出する。抽出液を水洗し、乾
燥して溶媒を留去する。残渣をシリカゲル350g
のカラムクロマトで処理し、展開液、クロロホル
ム：メタノール（９：１）混合液で流出した部分
より、
式
で表わされるＮ，N′−〔ジチオビス（エチレンイ
ミノカルボニルエチレン）〕ビス〔２，４−ジヒ
ドロキシ−３，３−ジメチルブチルアミド〕４，
４−ジニコチネートの無色粉末3.24gを得る。
元素分析 C34H48N6O10S2
計算値 C53.39，H6.33，N10.99，S8.38
実験値 C53.18，H6.15，N10.57，S8.15
IRスペクトル（KBr法）
第２図参照
NMRスペクトル
δＣＤ３ＣＯＣＤ３ ＴＭＳ；
1.06（6H，ｓ），1.12（6H，ｓ）
2.46（4H，ｔ，6.4Hz）
2.82（4H，ｔ，6.4Hz）
3.50（8H，ｍ）
4.10（2H，ｄ，3.6Hz）
4.27（4H，ｓ）
5.34（2H，ｄ，3.6Hz）
7.52（2H，ｄ，ｄ，8.2Hz，5.1Hz）
7.78（4H，ｍ）
8.34（2H，ｄ，ｔ，8.2Hz，1.9Hz
8.80（2H，ｄ，ｄ，5.1Hz，1.9Hz
9.20（2H，ｄ，1.9Hz）
FD−MS
ｍ／ｅ＝765（Ｍ＋１）＋ [Table] When administering this drug, it can be processed into various dosage forms such as capsules, tablets, powders, injections, etc. using known formulation techniques. The dosage of this drug varies depending on the administration method, but
It is sufficiently effective at doses of 200 to 2000 mg/day/person. The present invention will be explained below with reference to Examples. Example 1 Dissolve 6.50 g of pantethine in 65 ml of pyridine, add 10.0 g of nicotinic acid chloride hydrochloride,
Heat and stir at 40-45°C for 2 hours. After cooling, the precipitated crystals are filtered off, and the filtrate is poured into 300 ml of 5% sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract is washed with water, dried and the solvent is distilled off. Silica gel residue
After treatment with 450g column chromatography and development, N,N'-[dithiobis(ethyleneiminocarbonylethylene)]bis[2,4-dihydroxy-3, 3-dimethylbutyramide]2,
Colorless powder of 2',4,4'-tetranicotinate
Get 7.10g. Elemental analysis C 46 H 54 N 8 O 12 S 12 Calculated value C56.65, H5.58, N11.49, S6.58 Experimental value C56.26, H5.68, N10.98, S6.58 IR spectrum (KBr 1.30 (12H, s) 2.45 (4H, m) 2.70 (4H , m) 3.50 (8H, m) 4.38 (4H , s) 5.32 (2H, s) 7.50 ( 8H, m) 8.35 (4H, m) 8.84 (4H, m) 9.30 (4H, m) Field desorption mass spectrum (hereinafter abbreviated as FD-MS) m/e=975 (M+1) + Example 2 Dissolve 5.54 g of pantethine in 50 ml of pyridine, add 1.78 g of nicotinic acid chloride hydrochloride,
Heat and stir at 40°C for 1 hour. Next, 2.49 g of nicotinic acid chloride hydrochloride was added to the reaction solution, and
Heat and stir at 40°C for an hour. After cooling, the precipitated crystals are filtered off, and the filtrate is poured into 250 ml of 5% sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract is washed with water, dried and the solvent is distilled off. 350g of silica gel from the residue
From the part treated with column chromatography and flowing out with the developing solution and chloroform:methanol (9:1) mixture, the formula N,N′-[dithiobis(ethyleneiminocarbonylethylene)]bis[2,4-dihydroxy-3,3-dimethylbutyramide]4,
3.24 g of colorless powder of 4-dinicotinate is obtained. Elemental analysis C 34 H 48 N 6 O 10 S 2 Calculated values C53.39, H6.33, N10.99, S8.38 Experimental values C53.18, H6.15, N10.57, S8.15 IR spectrum (KBr method) See Figure 2 NMR spectrum δ CD3COCD3 TMS ; 1.06 (6H, s), 1.12 (6H, s) 2.46 (4H, t, 6.4Hz) 2.82 (4H, t, 6.4Hz) 3.50 (8H, m) 4.10 (2H, d, 3.6Hz) 4.27 (4H, s) 5.34 (2H, d, 3.6Hz) 7.52 (2H, d, d, 8.2Hz, 5.1Hz) 7.78 (4H, m) 8.34 (2H, d, t , 8.2Hz, 1.9Hz 8.80 (2H, d, d, 5.1Hz, 1.9Hz 9.20 (2H, d, 1.9Hz) FD-MS m/e=765 (M+1) +
第１図、第２図は、それぞれ、実施例１、実施
例２で得られた目的化合物のIRスペクトル図で
ある。
FIG. 1 and FIG. 2 are IR spectra of the target compounds obtained in Example 1 and Example 2, respectively.
Claims (1)
コチノイル基を意味する。但し、R1，R2，R′1お
よびR′2が同時に水素原子であることはない。）で
示されるニコチノイルパンテチン誘導体又はその
酸付化塩。 ２ 式 で表わされる特許請求の範囲第１項記載の化合
物。 ３ 式 で表わされる特許請求の範囲第１項記載の化合
物。[Claims] 1. General formula (In the formula, R 1 , R 2 , R′ 1 and R′ 2 mean a hydrogen atom or a nicotinoyl group. However, if R 1 , R 2 , R′ 1 and R′ 2 are hydrogen atoms at the same time, nicotinoylpantethine derivatives or acidified salts thereof. 2 formulas The compound according to claim 1, which is represented by: 3 formulas The compound according to claim 1, which is represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP952279A JPS55102566A (en) | 1979-01-30 | 1979-01-30 | Nicotinoylpantethine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP952279A JPS55102566A (en) | 1979-01-30 | 1979-01-30 | Nicotinoylpantethine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55102566A JPS55102566A (en) | 1980-08-05 |
| JPS6157828B2 true JPS6157828B2 (en) | 1986-12-09 |
Family
ID=11722591
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP952279A Granted JPS55102566A (en) | 1979-01-30 | 1979-01-30 | Nicotinoylpantethine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS55102566A (en) |
-
1979
- 1979-01-30 JP JP952279A patent/JPS55102566A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS55102566A (en) | 1980-08-05 |
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